Apoptosis, or programmed cell death, typically occurs in the normal development and maintenance of healthy tissues in multicellular organisms. It is a complex process which results in the removal of damaged, diseased or developmentally redundant cells, in the absence of signs of inflammation or necrosis.
Intrinsic apoptotic pathways are known to be dysregulated in a variety of disorders, including cancer and lymphoproliferative disorders, neurodegenerative diseases, and autoimmune and inflammatory conditions such as multiple sclerosis and rheumatoid arthritis. Cancer cells, for instance, gain the ability to overcome or circumvent apoptosis and continue with inappropriate proliferation despite strong pro-apoptotic signals such as hypoxia, endogenous cytokines, radiation treatments and chemotherapy. Abnormally apoptotic resistant cells also have been linked to autoimmune and inflammatory disease. For instance, apoptosis-resistance has been observed in fibroblast-like synoviocytes in connection with rheumatoid arthritis (RA), and in keratinocytes in connection with psoriasis. Abnormally apoptotic resistant T-cells also have been observed in several autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, idiopathic thrombocytopenic purpura, and alopecia areata. Pathogenic effector cells also have demonstrated resistance to normal apoptotic cues. It is believed that resistance to normal apoptosis is caused, at least in part, by increased activity of anti-apoptotic pathways or expression of anti-apoptotic genes.
The caspases are an integral part of the apoptotic pathway. The caspases are a family of proteolytic enzymes from the class of cysteine proteases, which are known to initiate and execute apoptosis. In normal cells, the caspases are present as inactive zymogens, but are catalytically activated by any of several external signals. Caspase-activating signals include, for example, the release of cytokines or immunological agents following ligand-driven Death Receptor activation, or the release of mitochondrial factors, such as cytochrome C, following genotoxic, chemotoxic, or radiation-induced cellular injury.
The Inhibitors of Apoptosis Proteins (IAPs) constitute a family of proteins that inhibit the caspases, thereby suppressing cellular apoptosis. Because of their central role in regulating caspase activity, the IAPs are capable of inhibiting programmed cell death from a wide variety of triggers. The IAPs are believed to play a role in the loss of homeostatic or endogenous cellular growth control mechanisms, as well as resistance chemotherapeutic drugs and radiation therapy.
The IAPs contain one to three homologous structural domains known as baculovirus IAP repeat (BIR) domains. They may also contain a RING zinc finger domain at the C-terminus, with a capability of inducing ubiquitinylation of IAP-binding molecules via its E3 ligase function. The human IAPs known as XIAP, HIAP1 (also referred to as cIAP2), and HIAP2 (cIAP1) each have three BIR domains, and a carboxy terminal RING zinc finger. Another IAP known as NAIP, has three BIR domains (BIR1, BIR2 and BIR3), but no RING domain. Still other IAPs known as Livin, TsIAP and MLIAP have only a single BIR domain and a single RING domain.
The X chromosome-linked inhibitor of apoptosis (XIAP) is an example of an IAP which can inhibit, by direct binding, the initiator caspase, known as caspase-9, and the effector caspases, known as Caspase-3 and Caspase-7. It is via the BIR3 domain that XIAP binds to and inhibits caspase-9. The linker-BIR2 domain of XIAP inhibits the activity of caspases-3 and -7. The BIR domains have also been associated with the interactions of IAPs with tumor necrosis factor-receptor associated factor (TRAFs)-1 and -2, and to TAB1, as adaptor proteins effecting survival signaling through NFkB activation. XIAP also can induce the removal of caspases by way of the E3 ligase activity of the RING zinc finger domain, which induces ubiquitinylation-mediated proteasomal degradation.
The IAPs thus function as a direct brake on the apoptosis cascade by inhibiting active caspases and re-directing cellular signaling to a pro-survival mode. The sustained over-expression of one or more members of the IAP family of proteins, therefore, allows diseased cells, such as cancer cells and cells involved in autoimmune disease, to avoid apoptosis. In fact, IAP overexpression has been demonstrated to be prognostic of poor clinical outcome in multiple cancers. Furthermore, suppressing IAP expression through RNA antisense or siRNA strategies sensitizes tumor cells to a wide variety of apoptotic insults including chemotherapy, radiotherapy, and ligand-mediated activation of the death receptors. In the case of XIAP, this has been shown in cancers as diverse as leukemia and ovarian cancer. Over expression of cIAP1 and cIAP2 also has been observed in a diverse variety of malignancies, including medulloblastomas, renal cell carcinomas, glioblastomas, and gastric carcinomas. For these reasons, the IAPs are valid therapeutic targets and compounds that inhibit their expression or function are believed to have significant utility in the treatment of proliferative diseases associated with dysregulated apoptosis, including cancer, autoimmune, and inflammatory diseases.